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FDA-NIH EFFORT TO CAPTURE THE GLOBAL CLINICAL
EXPERIENCE OF DRUG REPURPOSING TO FACILITATE
DEVELOPMENT OF NEW TREATMENTS FOR NEGLECTED
INFECTIOUS DISEASES (INCLUDING NEGLECTED
TROPICAL DISEASES AND EMERGING THREATS)
NEEDS AND OPPORTUNITIES
Dr Nathalie Strub Wourgaft – Medical Director
The concept of Neglected Diseases:
A R&D gap
Poorest of the poor
Living in remote areas
Socioeconomic burden on family and community
Marginalized & voiceless patients
Many Neglected Diseases at various control stages
List of 17
Buruli ulcer, Chagas disease Cysticercosis/taeniasis,
Dengue, Dracunculiasis, Echinococcosis, Fascioliasis
Human African trypanosomiasis, Leishmaniasis,
Leprosy, Lymphatic filariasis, Onchocerciasis,
Rabies, Schistosomiasis
Soil-transmitted helminthiasis, Trachoma
Yaws
Other neglected conditions
Mycetoma, snake bite, scabies, chronic suppurative
otitis media, podoconiosis
Amebiasis, Giardiasis, Cryptosporidium, Cholera,
Shigella, E. coli enterotoxigenic, E. coli enteriaggregative
enteropathogenic, Campylobacter, Non-typhoidal
Salmonella enterica , Typhoid and paratyphoid fever,
Rotavirus
WHO NTDs Diarrheal diseases
Other neglected diseases
Leptospirosis, Bartonellosis, Bovine tuberculosis in
humans, Relapsing fever, Japanese encephalitis, Yellow
fever, Other arboviral infections, Viral hemorrhagic fevers,
Strongyloidiasis, Loiasis, Toxocariasis and larva migrans,
Balantidiasis, Paracoccidiomycosis, Myiasis, Tungiasis,
TB, HIV malaria
The «big 3»
0
-2
-2
19
4
4
2
2
1
-1
-5
-9
7
6
3
1
3
2
0
-2
0
-1
1
-6
Genitourinary system
Neuropsychiatric disorders
Musculoskeletal diseases
Digestive diseases
Neoplasms
Neglected diseases
Cardiovascular diseases
Diabetes mellitus
Sense organ disorders
Respiratory diseases (non-infectious)
HIV/AIDS
Infectious and parasitic diseases
New chemical entities
New products
NCEs and New Products Deficit Analysis
Source: The drug and vaccine landscape for neglected diseases (2000—11): a systematic assessment;
Dr Belen Pedrique et al; the Lancet 2013. Deficit analysis was not part of the published version.
A major deficit persists for
anti-infectives
Deviation from expectation in percent
Approved products (2000-2011)
A deficit persists for neglected and infectious diseases
Approved products by category (2000-2011)
25 (67%) of recently approved
products for NDs consisted in
New Formulations, New Indications or
FDC
New indications approved products (2000-2011)
Indication (Disease) Products Galenic form
Leishmaniasis
Paromomycin (LV) Inj. 375mg/ml
Miltefosine (LV) Capsule 10mg&50mg
Miltefosine (Additional
Indication=Cutaneous L) Capsule 10mg&50mg
Human African
trypanosomiasis
Nifurtimox-Eflornithine Combination Therapy
(NECT) Nifurtimox new indication in
association
Leprosy Thalidomid Tablets
Acute Diarrhoea Zinc sulfate
oral liquid, in 10 mg per unit
dosage forms; tablet, in 10mg per
unit dosage form
Cholera Tosufloxacin tosilate hydrateFine Granules 15% for Pediatric
(Ozex)
TB Moxifloxacin (as hydrochloride) Tablets 400mg
Levofloxacin Tablets 250mg and 500 mg
Ofloxacin Tablets 200mg and 400 mg
Atovaquone&ProguanilTablets adults and paediatric
tablets for > 11 kg
Atovaquone&Proguanil film-coated tablets. (Malarone®
Enfants) 5-11kg 2003 FDA
10 (27%) of recently approved
products for NDs consisted in
New Indications (including pediatric
one) combinig :
- Extension of anti-infectives
- New indication
Neglected Diseases:
Treatment Limitations 10 Years Ago
We Need Safe, Effective, Easy-to-Use Drugs
Melarsoprol
Ineffective (resistance)
Toxic
Expensive
Painful when delivered
Difficult to use
Not registered in
endemic regions
Restricted by patents
Credit
Dr. Jannin, WHO
paromomycin
DNDi Portfolio-Building Model: Address Immediate Patient Needs & Deliver Innovative Medicines
Long-
term
projectsMedium-
term
projects
Short- term
projects
• New chemical
entities (NCEs)
• New formulations
(fixed-dose
combinations)
• New indications of
existing drugs
• Completing registration
dossier
• Geographical extension
Advantages of repurposing drugs at the clinical stage
Ref Nwiaka, Ridley
.Nat Rev Drug Discov 2003 Nov;2(11):919-28
Saving time to patients by
• De-risking (safety)
• Increasing chances of
success
• Saving costs
Miltefosine for Visceral Leishmaniasis (VL)
Phase 1 showing the need to administer tid to prevent digestive side effects and maximum
dose of 150mg/day (planned for oncology)
1986: development of a model to infect macrophages with leishmanial donovani (Croft)
1987: Alkyl phospholipids identified as possible candidates (Croft et al.)
1990s: Initially developed in several cancer indications with insufficient efficacy in phase II trials
1992: cure in mice with L donovani and L infantum (Kuhlencord et al)
1998, 1999, 2002, 2011: tested in clinical trials for VL, first by Sundar – Policy change for its
use in combination in India has now been granted
Developped by ASTA Medica- Zentaris later Paladin –who applied for NDA in 2013 and was
granted the PRV –
No new phase 1 – additonal PK data derived from CTs in Leishmanaisis patients
Generic drug development timelines for VLA significant time gain for repurposed drugs
The process of repurposing … example 1: HAT
A pragmatic and opportunistic scientific approach
1922: suramin
1941: pentamidine
1949: melarsoprol (effective but toxic)
mid-1970s: nifurtimox (registered for Chagas disease)
1981: eflornithine (developed for cancer – nor efficacy but promising in
reducing hair growth - developed as a topical cream for hirsutism) –
shown effective in HAT- registered in 1990 for HAT and cream for
hirsutism in 2000
2002: study in Uganda with MSF on 3 combinations
2009: Epicentre, and DNDi test nifurtimox-eflornithine combination in
a non inferioritiy trial against eflornithine – NECT added to the WHO
essential list and 1st line treatment
2009: fexinidazole, rediscovered after datamining of 700
nitroimidazole compounds, now in development in Man for stage 2
HAT
The process of repurposing … example 2
A pragmatic and opportunistic scientific approach
+ advocacy work + industrial partner Mycetoma
But are there any risks?
Scientifically : … if data from the repurposed compound are not solid … (but
this can be evaluated) – especially regarding the safety documentation
Regulatory: … acceptability of the NDA dossier will depend on the stage
from “repurposing”
Different for a licensed drug vs non licensed vs licensed since a long time
For the Industry: emergence of new safety signals (e.g due to different
population)
For the patient and public health system: affordability and sustainable
production
In conclusion …
The gap for safe and effective treatments for NDs or Neglected patients exist !
Accessing clinical candidates is an opportunity to shortcut the R&D process and accelerate
therefore access to needed treatments
Anticipation of regulatory needs and access plan are crucial
Repurposing has already shown its benefit for NTDs, and should be encouraged